Liver function improver

ABSTRACT

A liver function improver, food, or drink comprising, as an effective ingredient, a dioxabicyclo[3.3.0]octane derivative, such as sesamin, sesaminol espisesamin, episesaminol, sesamolin, 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.

This application is a divisional of application Ser. No. 07/555,586,filed Jul. 20, 1990, now U.S. Pat. No. 5,180,588.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a liver function improver comprising,as an effective ingredient, dioxabicyclo[3.3.0]octane derivative, and toa food or drink containing this derivative having a liverfunction-improving action, a cholesterol level-reducing action, and/or aneutral fat level-reducing action.

2. Description of the Related Art

The liver is the largest substantial organ of a human body, in additionto the brain, and has various functions such as a detoxifying action,carbohydrate metabolism, protein metabolism, the formation and secretionof bile, the formation of blood coagulation factors, hormone-controllingaction, and the action of storing various living body constituents suchas fat, glycogen, proteins, and vitamins. These functions are acutely orchronically impeded by viruses, drugs, poisons, excessive intake ofalcohol, malnutrition, liver circulatory system troubles, bile ductocclusion and the like, and as a result, there appear such diseases asviral hepatitis, drug doxic hepatitis, alcoholic hepatitis, congestivehepatitis, liver disorder due to a stagnation of hepatic juice fattyliver, interus, and finally, hepatocirrhosis.

For example, to remedy liver disorder caused by alcohol, there has beenadopted not only a method of controlling an intake of meat fat and anexcessive intake of alcohol, but also a medicinal therapy usingantihistamic agents, barbituric acid salts, adenosine triphosphate(ATP), pyrazole, a mixture of dihydroxy acetone and riboflavin,glucronic acid, arginine hydrochloride, and amino acid preparations suchas glutathione. Nevertheless, the effects of these drugs are notsatisfactory, and there is no certain remedial method other than acontrol of an excessive intake of alcohol. As one of the causes of liverdisorder brought on by drugs and poisons, there can be mentioned theformation of a harmful oxygen free radical, and accordingly, a largequantity of glutathione is administered for theraphy of toxicoses andallergic diseases. Especially, for a protection of cells, glutathionereduces or extinguishes an active oxygen species or free radical byglutathione peroxidase, or glutathione reacts with a poison throughglutathione-S-tranferase and discharges the poison from cells in theform of a glutathione conjugate, to exert the intended function wherebyantioxidation, detoxification and a protection from radiation damage canbe achieved. Nevertheless, even if glutamine per se is administered, thehalf-life is short (only several minutes) and tissue glutathione is noteffectively increased. Accordingly, the development of glutathionederivatives and the like is now under investigation.

Under the above circumstances, however, the development of a novel liverfunction improver is urgently required.

SUMMARY OF THE INVENTION

Therefore, a primary object of the present invention is to provide anovel liver function improver and a food having a liverfunction-improving action.

Since the liver-derived enzyme activity [glutamic-oxaloaceticaminotransferase (GOT) and glutamic-pyruvic aminotransferase (GPT)] insera of mouse and rat is increased by liver disorder, to obtain theabove-mentioned object, the inventors searched for a liver functionimprover by using GOT and GPT as indications, and as a result, foundthat a dioxabicyclo[3.3.0]octane isolated from sesame seeds, sesamelees, and sesame oil, or a synthesized dioxabicyclo[3.3.0]octanederivative, has a liver function-improving action, a cholesterollevel-reducing and a neutral fat level-reducing action, and is verysafe.

More specifically, in accordance with the present invention, there isprovided a liver function improver comprising, as an effectiveingredient, a dioxabicyclo[3.3.0]octane derivative represented by thefollowing general formula (1): ##STR1## wherein R¹, R², R³, R⁴, R⁵, andR⁶ independently represent a hydrogen atom or an alkyl group having 1 to3 carbon atoms, or R¹ and R² and/or R⁴ and R⁵ together form a methylenegroup or an ethylene group, and n, m and l are 0 or 1.

Furthermore, in accordance with the present invention, there is provideda food containing the above-mentioned derivative.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As the dioxabicyclo[3.3.0]octane, in the present invention, sesamin,sesaminol, episesamin, episesaminol, sesamolin,2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octanecan be used. These derivatives can be used alone or in the form of amixture of two or more thereof.

The compound of the present invention, and an extract composed mainly ofthe compound of the present invention, can be obtained according to thefollowing procedures. First, an extract composed mainly of the compoundof the present invention can be obtained from sesame oil according to amethod comprising extracting sesame oil with an organic solventsubstantially immiscible with sesame oil and capable of extracting anddissolving the compound of the present invention, and concentrating theextract. As the organic solvent, there can be mentioned, for example,acetone, methylethylketone, diethylketone, methanol and ethanol. Forexample, an extract composed mainly of the compound of the presentinvention can be obtained by mixing sesame oil homogeneously with anorganic solvent as mentioned above, allowing the mixture to stand at alow temperature, carrying out a phase separation according to acustomary process, and removing the solvent from the solvent fraction byevaporation. More specifically, sesame oil is dissolved in 2 to 10volumes, preferably 6 to 8 volumes of acetone, and the solution isallowed to stand at -80° C. overnight. As a result, the oil component isprecipitated, and the organic solvent is removed from the obtainedfiltrate by distillation, whereby an extract composed mainly of thecompound of the present invention is obtained. Alternatively, sesame oilis mixed with hot methanol or hot ethanol, the mixture is allowed tostand at room temperature, and the solvent is removed from the solventfraction to obtain an extract composed mainly of the compound of thepresent invention. More specifically, sesame oil is mixed with hotmethanol (higher than 50° C.) or hot ethanol (higher than 50°) in avolume 2 to 10 times, preferably 5 to 7 times, as large as the volume ofthe sesame oil to effect a violent extraction. The phase separation iseffected by a phase separation when standing at room temperature or acentrifugal separation according to customary procedures, and thesolvent is removed from the solvent fraction by distillation to obtainan extract composed mainly of the compound of the present invention.Furthermore, the supercritic gas extraction can be utilized. Thecompound of the present invention can be obtained from an extract asmentioned above by treating the extract by a customary method such ascolumn chromatography, high performance liquid chromatography,recrystallization, distillation, or liquid-liquid countercurrentdistribution chromatography. More specifically, by using a reversedphase column (5C₁₈) and methanol/water (60/40) as the eluent, theextract is subjected to high performance liquid chromatography, thesolvent is removed by distillation, and the obtained crystal isrecrystallized from ethanol to obtain the compound used in the presentinvention, such as sesamin, episesamin, sesaminol or episesaminol. Thesesame oil used in the present invention can be either a purifiedproduct or a crude product. Furthermore, sesame seeds or sesame less(defatted sesame seeds having a residual oil content of 8 to 10%) can beused. In this case, sesame seeds or sesame less are pulverized ifnecessary, and then subjected to the extraction according to customaryprocedures using an any solvent, for example, a solvent as mentionedabove with respect to the extraction from sesame oil. The extractionresidue is separated, and the solvent is removed from the extract byevaporation or the like to obtain an extraction product. The compoundused in the present invention, for example, sesamin, sesaminol,episesamin, episesaminol, sesamolin,2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane,can be obtained from a sesame seed extract, a sesame lee extract or acrude sesame oil extract according to the same procedures as describedabove. Moreover, the compound used in the present invention can beobtained from a by-product formed in the sesame oil-preparing process.

The process for the purification of the compound of the presentinvention and the process for obtaining the extract are not limited tothose mentioned above, and the compound used in the present inventionand the extract composed mainly of the compound of the present inventionare not limited to those obtained from sesame oil, sesame lees andsesame seeds, but as is apparent to persons with ordinary skill in theart, all natural substances containing the compound used in the presentinvention can be used. For example, there can be mentioned Acanthopanaxsessiliflorus, paulowina, Ginkgo-biolobu and Piper lonum.

The following processes can be adopted for the synthesis of the compoundof the present invention.

For example, sesamin and episesamin can be synthesized according to theprocess of Beroza et al. [J. Am. Chem. Soc., 78, 1242 (1956)].Pinoresinol [in the general formula (I), R¹ and R⁴ represent H, R² andR⁵ represent CH₃, and n, m and l are zero] can be synthesized accordingto the process of Freundenberg et al. [Chem. Ber., 86, 1157 (1953)].Furthermore, syringaresinol [in the general formula (I), R¹ and R⁴represent H, R², R³, R³, R⁵ and R⁶ represents CH₃, n is zero, and eachof m and l is 1] can be synthesized according to the process ofFreundenberg et al [Chem. Ber., 88, 16 (1955)].

The compound used in the present invention also can be used in the formof a glycoside. Furthermore, compounds used in the present invention canbe used alone or in combination with other liver function improver or afunctional factor of a food.

The liver function improver of the present invention can be orallyadministered, or non-orally administered, for example, by intramuscularinjection, hypodermic injection or intravenous injection.

The dosage depends on the state of a person to whom the liver functionimprover is administered, but in general, in the case of the oraladministration, the dosage is 1 to 100 mg/day, and in the case of thenon-oral administration, the dosage is 0.1 to 20 mg/day. For thepreparation of an injection, a solubilizing agent for a drug, forexample, a nonionic surface active agent, can be used. Morespecifically, the compound of the present invention is dissolved underheating in a nonionic surface active agent such as POE (60) hardenedcastor oil or POE sorbitan-monooleate in a volume 80 times as large asthe volume of the compound of the present invention, and the solution isdiluted with a physiological saline to form an injection solution. Anisotonic agent, a stabilizer, an antiseptic agent, and an alagesicagent, can be incorporated according to need. If necessary, the compoundof the present invention can be formed into an emulsion, a capsule, adust, a granule or a tablet.

In view of the cholesterol level-reducing action and the neutral fatlevel-reducing action, it is considered preferable to incorporate thecompound of the present invention into foods containing oil and fat,although the kind of food into which the compound of the presentinvention is incorporated is not limited. For example, there can bementioned natural foods such as meat, fish and nut, foods to which oiland fat are added at the cooking step, such as Chinese meals, Chinesenoodles and soups, foods cooked by using oil and fat as the heatingmedium, such as Japanese fried foods, fried bean curd, Chinese friedrice, doughnuts and fried dough cakes, oil and fat foods or processedfoods to which oil and fat are added at the processing step, such asbutter, margarine, mayonnaise, dressings, chocolate, instant noodles,caramels, biscuits and ice creams, and foods onto which oil and fat aresprayed or coated at the processing step, such as sliced and dried ricecakes, hard biscuits and bean-jam buns. Since the extract composedmainly of the compound of the present invention comprises effectiveingredients inherently contained in an edible oil and fat or extractsthereof, addition of the extract of the present invention can be easilyaccomplished and the extract of the present invention can easily addedto the above-mentioned foods. Note, the foods are not limited to oil- orand fat-containing foods, and the extract of the present invention canbe added to all foods to provide foods having a liver function-improvingaction, a cholesterol level-reducing action, and a neutral fatlevel-reducing action.

In the present invention, the amount of the compound of the presentinvention is not particularly critical, but preferably the amount of thecompound of the present invention is 0.001 to 20% by weight, especially0.01 to 10.0% by weight, based on the food to which the compound of thepresent invention is added. It the amount of the compound of the presentinvention is smaller than 0.001% by weight, the effect is low, and ifthe amount is larger than 20% by weight, the taster and flavor of somefoods are adversely affected. Preferably, the content of the compound inthe extract is at least 25%. Moreover, the compound of the presentinvention can be converted to a cyclodextrin inclusion compound and theformed powder can be used.

The significance of the present invention will now be described. Butteris a very popular food prepared from butter fat or cream, a milk solidand a natural colorant, and further, contains sodium chloride. The fatcontent in butter is usually about 80%. For the preparation of butter,cream obtained by centrifugal separation is subjected to stirring(churning) directly or after lactic acid fermentation, whereby the fatglobule membrane is destroyed and fat is fused into particles, andsodium chloride is added to the churned cream and kneading (working) iscarried out to obtain a product having a homogeneous texture. Thethus-prepared butter is a popular food because of its peculiar andcharacteristic taste and flavor, but since butter has a very highcholesterol content (the cholesterol level is about 220 mg/100 g),health experts recommend eliminating butter from a food or reducing thecontent of butter for lowering or controlling the intake of cholesterol.If the compound of the present invention or the extract composed mainlyof the compound of the present invention is added to butter, an effectof preventing the increase of the cholesterol level after the intake ofbutter can be obtained. Moreover, since the product of the presentinvention is not an imitation food, the inherent taste and flavor ofbutter can be retained. The compound of the present invention or theextract composed mainly of the compound of the present invention can beadded at any step of the butter-preparing process, but the addition atthe kneading operation (working) is especially preferable.

The present invention also can be applied to the improvement of a foodquality. Mayonnaise is prepared by mixing edible oil with vinegar byusing egg yolk lecithin as an emulsifier, and sugar, table salt, mustardand white pepper are used as additives. Mayonnaise and dressings are o/wtype emulsions in which the water layer is a main component, andaccording to JAS standards, mayonnaise is defined as a product having anoil content, which is formed by using an egg as the emulsifier, anddressings are divided into a salad dressing having an oil content of atleast 65%, for which an emulsifier other than an egg can be used, and aFrench dressing formed without using egg. Here, a problem resides in theuse of the egg yolk as the emulsifier. It has been experimentally provedthat the serum cholesterol level in the human body is increased by theintake of egg yolk. Therefore, the use of a large quantity of egg yolkto increase the quality of mayonnaise is not allowed. Nevertheless, ifthe compound of the present invention or the extract composed mainly ofthe compound of the present invention is added to edible oil used formayonnaise, it becomes possible to prevent an increase of thecholesterol level after the intake of mayonnaise, and it also becomespossible to increase the amount of egg yolk used for mayonnaise, andthus increase the quality of the mayonnaise. Furthermore, the quality ofa salad dressing prepared by using egg yolk as the emulsifier can beimproved by incorporating the compound or extract of the presentinvention.

The effect of the compound of the present invention or the extractcomposed mainly of the compound of the present invention as thefunctional factor can be increased by a combined use thereof with othersubstances, and the combined use of a fatty acid having 16 to 20 carbonatoms and 1 to 3 double bonds in the carbon chain, especiallyτ-linolenic acid (6,9,12-octadecatrienoic acid) or dihomo-τ-linolenicacid (8,11,14-eicosatrienoic acid), is preferred. In this case, the acidcan be used directly or in the form a salt of sodium, potassium orammonium or an ester such as a methyl ester or an ethyl ester. Moreover,oils and fats containing these fatty acids can be used.

The cholesterol level-reducing and neutral fat level-reducing actions ofthe compound of the present invention, the extract composed mainly ofthe compound of the present invention, and the food containing thecompound or extract have been explained. As described in Japanese PatentApplication No. 1-052950, the compound of the present invention or theextract composed mainly of the compound of the present invention can bean inhibitor for specifically inhibiting a Δ⁵ -desaturase for convertingdihomo-τ-linolenic acid to arachidonic acid. It is expected that variouspharmacological effects will be obtained by an increase of theeicosanoide of dihomo-τ-linolenic acid brought about by an increase ofthe content of dihomo-τ-linolenic acid. For example, an antiinflamatoryaction, an anti-thrombosis action, and a hypotensive action can beexpected, and the compound of the present invention and the extractcomposed mainly of the compound of the present invention can be used asa remedy for related diseases, such as inflammatory diseases,heartvascular and thrombotic diseases, mental diseases, chest andprostate diseases, diabetes, endometritis, malnutrition, menstrualdisorders, and malignant tumors. Accordingly, as the function attainedby the present invention, there can be mentioned the anti-thrombosisaction, the antiinflammatory action, and the hypotensive action.Furthermore, these actions can be significantly enhanced by the effectderived from prostaglandin I by the combined use with τ-linolenic acidand dihomo-τ-linolenic acid.

The compound of the present invention has a very high activity; this ismade obvious from the fact that, even if sesamin was continuouslyadministered (oral administration) to 7-weeks-old ICR male mice at adosage of 2.14 g/day/kg continuously for two weeks, no abnormal symptomswere observed.

The present invention will now be described in detail with reference tothe following examples.

EXAMPLE 1

To 16.5 kg of sesame oil was added 94.5 l of hot methanol (60° C.), themixture was violently stirred to effect extraction, and then allowed tostand at room temperature overnight. The organic solvent was removedfrom the upper methanol layer by distillation using a rotary evaporator,to obtain 424 g of an extract composed mainly of the compound of thepresent invention. Then the extract was dissolved in 3.2 l of acetone,the solution was allowed to stand at -80° C. overnight, and the organicsolvent was removed by distillation from the filtrate obtained by thefiltration to obtain 103 g of an extract composed mainly of the compoundof the present invention. When the compound of the present invention wasanalyzed, it was found that the compound of the present inventioncomprised 19.6% of sesamin, 30.6% of episesamin and 10.2% of sesaminoland episesaminol based on the extract, and the content of the compoundof the present invention in the extract was 60.4%.

Eight-weeks-old male mice (CD-1 mice supplied by Nippon Charles River)were raised for one week with an ordinary feed (CE-2 feed supplied byNippon Clea). The mice were then divided into 4 groups, each consistingof 10 mice, and the mice of one group were raised with the same ordinaryfeed, and the mice of the other three groups were raised with a highcholesterol feed having 1% of cholesterol, 0.2% of cholic acid and 5% ofolive oil incorporated therein. Of the three groups to which thehigh-cholesterol feed was given, the two groups were raised with a feedobtained by incorporating 0.4 or 0.6% of the above-mentioned extractcomposed mainly of the compound of the present invention into thehigh-cholesterol feed. After two weeks' growth, the mice were fasted for15 hours and blood was collected. The GOT and GPT activities in theserum were analyzed by an automatic biochemical analysis apparatus(Model 7050 supplied by Hitachi). The results are shown in Table 1, andas seen from these results, increases of GOT and GPT were controlled byusing the compound of the present invention.

                  TABLE 1                                                         ______________________________________                                                                 High-chole-                                                                             High-chole-                                                         sterol feed                                                                             sterol feed                                                         + 0.4% of + 0.6% of                                         Ordinary                                                                              High-chole-                                                                             sesame oil                                                                              sesame oil                                        feed    sterol feed                                                                             extract   extract                                    ______________________________________                                        GOT (IU/L)                                                                             72 ± 24.6                                                                            161 ± 48.8                                                                           136 ± 53.7                                                                         104 ± 26.1                            GPT (IU/L)                                                                             24 ± 5.5                                                                             151 ± 66.7                                                                            68 ± 18.7                                                                          82 ± 39.1                            ______________________________________                                    

EXAMPLE 2

In the same manner as described in Example 1, mice were raised for oneweek with the ordinary feed, and the mice were divided into four groups,each consisting of 10 mice. The mice of one group were raised with thesame ordinary feed, and the mice of the remaining three groups wereraised with a high-cholesterol feed formed by adding 1% of cholesterol,0.2% of cholic acid and 5% of evening primrose oil to the ordinary feed.A feed formed by adding 0.4 to 0.6% of a purified mixture comprising61.5% of sesamin and 38.0% of episesamin to the high-cholesterol feedwas given to the mice of the two groups among the three groups to whichthe high-cholesterol feed was given. After two weeks' growth, the micewere fasted for 15 hours and blood was collected. The GOT and GPTactivities in the serum were measured, and the results are shown inTable 2. As seen from these results, the increase of GOT by thehigh-cholesterol feed was controlled by using the mixture of sesamin andepisesamin.

                  TABLE 2                                                         ______________________________________                                                                 High-chole-                                                                             High-chole-                                                         sterol feed                                                                             sterol feed                                       Ordinary                                                                              High-chole-                                                                             + 0.4% of + 0.6% of                                         feed    sterol feed                                                                             sesamin   sesamin                                    ______________________________________                                        GOT (IU/L)                                                                             105 ± 31.8                                                                           141 ± 35.8                                                                           112 ± 35.6                                                                         87 ± 13.2                             GPT (IU/L)                                                                             29 ± 5.1                                                                              58 ± 14.2                                                                            64 ± 23.1                                                                         45 ± 16.2                             ______________________________________                                    

EXAMPLE 3

Eight-weeks-old male rats of the SD line (supplied by Nippon Clea) wereraised for 1 week with an ordinary feed, and the rats were divided into4 groups, each consisting of 6 rats. The rats of one group were raisedwith the same ordinary feed, and the rats of the remaining three groupswere raised with a high-cholesterol feed comprising 20% of casein, 10%of beef tallow, 59.9% of granulated sugar, 4.0% of a mineral mixture,0.85% of a vitamin mixture, 4.0% of a filter paper powder. 1.0% ofcholesterol and 0.25% of bile acid. A feed formed by adding 1.0 or 2.0%of the mixture of sesamin and episesamin used in Example 2 to theabove-mentioned high-cholesterol feed was given to the rats of twogroups among the three groups to which the high-cholesterol feed wasgiven. After 1 week's growth, blood was partially collected, and aftertwo weeks' growth, blood was wholly collected. Each blood collection waseffected after 17 hours' fasting. The GOT and GPT activities in theserum were measured. The results are shown in Table 3, and from theseresults, it is seen that the increase of GOT by the high-cholesterolfeed was controlled by using the mixture of sesamin and episesamin.

                  TABLE 3                                                         ______________________________________                                                                 High-chole-                                                                             High-chole-                                                         sterol feed                                                                             sterol feed                                       Ordinary                                                                              High-chole-                                                                             + 1.0% of + 2.0% of                                         feed    sterol feed                                                                             sesamin   sesamin                                    ______________________________________                                        After 1 week's raising                                                        GOT (IU/L)                                                                             119 ± 37.8                                                                           140 ± 48.2                                                                            76 ± 12.8                                                                          63 ± 11.5                            GPT (IU/L)                                                                              39 ± 9.9                                                                            23 ± 1.7                                                                             24 ± 3.4                                                                           26 ± 1.9                              After 2 weeks' raising                                                        GOT (IU/L)                                                                              83 ± 11.5                                                                           102 ± 37.8                                                                            81 ± 21.5                                                                          76 ± 12.1                            GPT (IU/L)                                                                              26 ± 4.3                                                                            21 ± 1.3                                                                             22 ± 2.3                                                                           27 ± 6.4                              ______________________________________                                    

EXAMPLE 4

Nine-weeks-old male CDF-1 mice (supplied by Nippon Clea) were raised for1 week, and the mice were divided into three groups, each consisting of7 mice. The mice of two groups other than the control group were raisedin a chamber filled with air containing 12 ppm of ethanol. After 1week's growth, the mice were fasted for 16 hours, and blood wascollected. The total cholesterol (T-CHO) content, the triglyceride (TG)content, the GOT and GPT activities and the total bilirubin content inthe serum were measured, and the results are shown in Table 4.

The increase of the triglyceride content, the total bilirubin content,GOT, and GPT by the administration of the alcohol was significantlyreduced. When the general motion of the mice was observed, it was seenthat in the ordinary feed-given group, 5 mice of the seven mice werefragged out, but in the sesamin-containing feed-given groups, the motionwas not different from the ordinary motion. Thus, a conspicuousdifference was found.

                                      TABLE 4                                     __________________________________________________________________________             Feed  Sesamin                                                                              Serum                                                            intake                                                                              intake total                                                            amount                                                                              amount serum           Serum                                            (g/mouse/                                                                           (mg/mouse/                                                                           CHOL   Serum TG total BIL                                                                             Serum GOT Serum GPT                      day)  day)   (mg/dl)                                                                              (mg/dl)  (mg/dl) (IU/L)    (IU/L)                __________________________________________________________________________    Ordinary feed                                                                          3.55  0      91.6 ± 8.8                                                                        58.6 ± 12.1.sup.                                                                    0.47 ± 0.15                                                                        149.7 ± 76.3  .sup.                                                                  26.1 ± 7.8         Ordinary feed                                                                          2.45  0      100.9 ± 10.2                                                                      237.3 ± 124.2.sup.++                                                                .sup. 1.61 ± 1.32.sup.+                                                            312.4 ± 203.8.sup.+                                                                  39.6 ± 31.9        + ethanol                                                                     Ordinary feed                                                                          2.43  24.3   89.4 ± 8.5                                                                        83.0 ± 19.0*.sup.+                                                                   0.41 ± 0.04*                                                                      81.6 ± 15.4**.sup.+                                                                  18.3 ± 1.6*        + ethanol +                                                                   + 1% of sesamin                                                               __________________________________________________________________________     Note                                                                          CHOL: cholesterol                                                             TG: triglyceride                                                              BIL: bilirubin                                                                to ordinary feed: .sup.+ P < 0.05 .sup.++ P < 0.01                            to ordinary feed +  ethanol: *P < 0.05 **P < 0.01                        

EXAMPLE 5

Eight-weeks-old male CDF-1 mice (supplied by Nippon Clea) were raisedfor 1 week and were divided into three groups, each consisting of 7mice. To two groups other than the control group, 1 mg/kg of carbontetrachloride was administered in the abdominal cavity. To one of thesetwo groups, simultaneously, 100 mg/kg of sesamin was forcibly orallyadministered. Then the mice were fasted for 16 hours and blood wascollected. The total cholesterol (T-CHO), the triglyceride (TG) content,GOT, GPT and the total bilirubin content in the serum were measured. Theresults are shown in Table 5.

                                      TABLE 5                                     __________________________________________________________________________    Evaluation of Resistance to Acute Loading of Carbon Tetrachloride                     T-CHO    TG       GOT      GPT       ALP      T-BIL                           (MG/DL)  (MG/DL)  (IU/L)   (IU/L)    (IU/L)   (MG/DL)                 __________________________________________________________________________    Control 105.00 ± 6.19                                                                       76.00 ± 8.27                                                                        122.9 ± 48.6                                                                        22.1 ± 4.9                                                                           227.40 ± 18.48                                                                      0.40 ± 0.13          Carbon tetra-                                                                         63.30 ± 6.92                                                                        48.90 ± 11.6                                                                        26468.0 ± 2071.6                                                                    28152.0 ± 1315.4                                                                     455.90 ± 45.37                                                                      2.90 ± 0.24          chloride                                                                      Carbon tetra-                                                                          84.00 ± 11.99**                                                                     5.70 ± 5.50*                                                                       25274.0 ± 2398.0                                                                    31750.0 ± 3731.2                                                                     500.90 ± 36.51                                                                      1.30 ± 0.42***       chloride +                                                                    sesamin                                                                       __________________________________________________________________________     Note                                                                          *p < 0.05 vs. CC14                                                            **p < 0.01 vs. CC14                                                           ***p < 0.001 vs. CC14                                                    

EXAMPLE 6

Male rats of the Wister line were divided into two groups (control groupand sesamin group), each consisting of 6 rats. The rats of the controlgroup were raised for 22 days with a basic feed and the rats of thesesamin group were raised for 22 days with a feed formed by adding 0.5%of sesamin to the basic feed. The rats were fasted overnight, and 1 g/kgof ethanol (20%) was forcibly orally administered. After 1 and 3 hours,blood was collected from the tail vein and the alcohol concentration inblood was measured. After 1 hour from the point of the administration,the ethanol concentration was 0.5 mg/ml in the control group but theethanol concentration was 0.27 mg/ml in the sesamin group. After 3 hoursfrom the point of the administration, the ethanol concentration was 0.12mg/ml in the control group but the ethanol concentration was 0.02 mg/mlin the sesamin group. Accordingly, it was confirmed that ethanoldisappeared more quickly in the sesamin group than in the control group.

EXAMPLE 7

Examples of the formulation of the compound of the present inventionwill now be described, though the present invention is not limited bythese formulation examples.

FORMULATION 1

With 20.5 g of silicic anhydride was mixed 0.5 g of the compound of thepresent invention, and 79 g of corn starch was added to the mixture.Then, 100 ml of a 10% solution of hydroxypropyl cellulose in ethanol wasadded to the mixture, and according to customary procedures, the mixturewas kneaded, extruded and dried to obtain a granule.

FORMULATION 2

With 20 g of silicic anhydride was mixed 7 g of the compound of thepresent invention, and 10 g of microcrystalline cellulose, 3.0 g ofmagnesium stearate and 60 g of lactose were added to the mixture. Themixture was formed into tablets having a diameter of 7 mm and a weightof 100 mg by using a single-shot tableting machine.

FORMULATION 3

In 200 g of a nonionic surface active agent (TO-10M supplied by NikkoChemicals) was dissolved 2.5 g of the compound of the present inventionunder heating at 122° C. Then, 4.8985 g of a sterilized physiologicalsaline solution was added to the solution and the mixture was thoroughlystirred. The liquid was sterilely distributed into vials, and the vialswere sealed to obtain injections.

EXAMPLE 8

In 180 ml of salad oil was dissolved 0.9 g of the extract composedmainly of the compound of the present invention, which was obtained inExample 1. Separately, a vessel was charged with one egg yolk, 3 g oftable salt, 1 g of mustard, sugar, a spice and a chemical seasoning, and3 ml of vinegar was added into the vessel and the mixture was stronglystirred by a whip to form a mayonnaise base. Then, 12 ml of vinegar and180 ml of the salad oil containing the compound of the present inventiondissolved therein were added to the mayonnaise base with stirring toobtain a mayonnaise containing the compound of the present invention.

EXAMPLE 9

To 100 g of a butter milk-free butter fat obtained at the stirringoperation (churning) in the butter-preparing process, 2 g of the extractcomposed mainly of the compound of the present invention, which wasobtained in Example 1 of the present invention, was added, and themixture was subjected to the kneading operation (working) to obtain abutter containing the compound of the present invention, which had ahomogeneous texture.

EXAMPLE 10

The mayonnaise containing the compound of the present invention, whichwas obtained in Example 8, and the butter containing the compound of thepresent invention, which was obtained in Example 9, were compared withthe mayonnaise and butter prepared without adding the compound of thepresent invention, and the differences of the taste and flavor wereevaluated by five experts. As a result, it was confirmed that theinherent quality was not influenced by the addition of the compound ofthe present invention.

EXAMPLE 11

Four-weeks-old male rats of the SD line were raised for 3 weeks with afeed containing 10% of the butter containing the compound of the presentinvention, which was obtained in Example 9 (compound-added group), or abutter not containing the compound of the present invention(compound-free group). After 3 weeks, the body weight, the liver weight,the plasma cholesterol content, the plasma triglyceride content and theplasma phospholipid content were measured. The results are shown inTable 6.

As apparent from the results shown in Table 6, even if the foodcontaining the compound of the present invention was given, there was nodifference of the increase of the body weight or the liver weight during3 weeks' raising and the growth was not influenced at all. Furthermore,the cholesterol and triglyceride levels in the plasma were reduced bygiving the food containing the compound of the present invention.

                  TABLE 6                                                         ______________________________________                                                      Compound-added                                                                           Compound-free                                                      group      group                                                ______________________________________                                        Initial body weight (g)                                                                       102 ± 3   103 ± 3                                       Final body weight (g)                                                                         272 ± 13  275 ± 11                                      Body weight increase (g)                                                                      170 ± 11  172 ± 10                                      Body weight increased per                                                                      8 ± 0     8 ± 0                                        day (g/day)                                                                   Total intake (g)                                                                              388 ± 9   384 ± 13                                      Intake per day (g/day)                                                                        18 ± 1    18 ± 1                                        Feed efficiency  0.43 ± 0.01                                                                             0.43 ± 0.01                                  Liver weight (g)                                                                              15.23 ± 0.52                                                                            14.87 ± 0.67                                  Plasma cholesterol level                                                                      76.2 ± 4.3                                                                              112.7 ± 4.9                                   (mg/dl)                                                                       Plasma triglyceride level                                                                     145.7 ± 21.5                                                                            214.3 ± 11.4                                  (mg/dl)                                                                       Plasma phospholipid level                                                                     211.4 ± 7.6                                                                             251.8 ± 17.9                                  (mg/dl                                                                        ______________________________________                                    

EXAMPLE 12

From the extract composed mainly of the compound of the presentinvention, which was obtained in Example 1, Δ⁵ -desaturase inhibitors,i.e., sesamin, episesamin, sesaminol and episesaminol, were obtainedaccording to the method described in Japanese Patent Application No.1-052950. Sesamine-containing mayonnaise and sesamin-containing butterwere prepared in the same manner as described in Examples 7 and 8 byusing 0.54 g and 1.2 g of sesamin, respectively. Similarly, foodscontaining the compounds, of the present invention singly or incombination were be obtained. The compound of the present invention wasa colorless (white) crystal and had no taste or smell. Accordingly, thecompound of the present invention did not have any influence on theinherent quality of the foods.

EXAMPLE 13

To 20 ml of water was added 2 g of β-cyclodextrin, and 0.2 g of sesamindissolved in a small amount of acetone was added to the mixture underagitation by a stirrer. The mixture was stirred at room temperature for4 hours and freeze-dried to obtain 2.2 g of a cyclodextrin inclusioncompound containing 10% of sesamin. A sesamin-containing juice wasprepared by adding 1 g of the obtained powder to 100 ml of a juice.

EXAMPLE 14

The procedures of Example 13 were repeated by using the compound of thepresent invention and the extract composed mainly of the compound of thepresent invention. Juices containing the compound of the presentinvention and the extract, respectively, were obtained.

EXAMPLE 15

In 82 g of a starting oil and fat material comprising 30% of ediblehardened soybean oil, 10% of edible hardened cotton seed oil, 40% ofsoybean salad oil, 10% of palm oil and 10% of corn oil, 1 g of sesaminwas incorporated and dissolved. Then, 15 g of water, 1.2 g of tablesalt, 0.3 g of monoglyceride, 0.1 g of lecithin, a trace of carotene,0.00001 g of a flavor and 1.4 g of a milk solid were added to thesolution, and the mixture was emulsified, rapidly cooled, and kneaded toobtain a sesamin-containing margarin.

We claim:
 1. A method for the prevention or treatment of fatty liver,liver disorders caused by alcohol, treatment of liver disorders causedby chemicals, acceleration of alcohol metabolism, or decrease of serumcholesterol or neutral fat comprising administering to a person in needof such treatment, an effective amount to prevent or treat fatty liver,liver disorders caused by alcohol, to treat liver disorders caused bychemicals, to accelerate alcohol metabolism, or to decrease serumcholesterol or neutral fat of a dioxabicyclo[3.3.0]octane derivativerepresented by the following general formula (I): ##STR2## wherein R¹,R², R³, R⁴, R⁵ and R⁶ independently represent a hydrogen atom or analkyl grouping having 1 to 3 carbon atoms, or R¹ and R² and/or R⁴ and R⁵together form a methylene group or an ethylene group, and n, m and l are0 or
 1. 2. The method as set forth in claim 1, wherein thedioxabicyclo[3.3.0]octane derivative is sesamin, sesaminol, episesamin,episesaminol, sesamolin,2-(3,4-methylenedioxy-phenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.3. The method according to claim 1, wherein a compound of the formula(I) is incorporated into a food or drink.
 4. A method for lowering aglutamic-oxaloacetic aminotransferase or glutamic-pyruvicaminotransferase value increased by a high cholesterol diet, comprisingadministering to a person in need of such treatment, an effective amountto lower a glutamic-oxaloacetic aminotransferase or glutamic-pyruvicaminotransferase value increased by a high cholesterol diet of adioxabicyclo[3.3.0]octane derivative represented by the followinggeneral formula (I): ##STR3## wherein R¹, R², R³, R⁴, R⁵ and R⁶independently represent a hydrogen atom or an alkyl group having 1 to 3carbon atoms, or R¹ and R² and/or R⁴ and R⁵ together form a methylenegroup or an ethylene group, and n, m and l are 0 or
 1. 5. The method asset forth in claim 4, wherein the dioxabicyclo[3.3.0]octane derivativeis sesamin, sesaminol, episesamin, episesaminol, sesamolin,2-(3,4-methylenedioxy-phenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.6. The method according to claim 4, wherein a compound of the formula(I) is incorporated into a food or drink.
 7. A method of decreasingglutamic-oxaloacetic aminotransferase, glutamic-pyruvicaminotransferase, serum total cholesterol, serum triglyceride or serumtotal bilirubin increased by an intake of alcohol, comprisingadministering to a person in need of such treatment, an effective amountto decrease glutamic-oxaloacetic aminotransferase, glutamic-pyruvicaminotransferase, serum total cholesterol, serum triglyceride or serumtotal bilirubin to increase by an intake of alcohol of adioxabicyclo[3.3.0]octane derivative represented by the followinggeneral formula (I): ##STR4## wherein R¹, R², R³, R⁴, R⁵ and R⁶independently represent a hydrogen atom or an alkyl group having 1 to 3carbon atoms, or R¹ and R² and/or R⁴ and R⁵ together form a methylenegroup or an ethylene group, and n, m and l are 0 or
 1. 8. The method asset forth in claim 7, wherein the dioxabicyclo[3.3.0]octane derivativeis sesamin, sesaminol, episesamin, episesaminol, sesamolin,2-(3,4-methylenedioxy-phenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.9. The method according to claim 7, wherein a compound of the formula(I) is incorporated into a food or drink.
 10. A method of decreasingserum total bilirubin increased by an intake of chemicals, comprisingadministering to a person in need of such treatment, an effective amountto decrease serum total bilirubin increased by an intake of chemicals ofa dioxabicyclo[3.3.0]octane derivative represented by the followinggeneral formula (I): ##STR5## wherein R¹, R², R³, R⁴, R⁵ and R⁶independently represent a hydrogen atom or an alkyl group having 1 to 3carbon atoms, or R¹ and R² and/or R⁴ and R⁵ together form a methylenegroup or an ethylene group, and n, m and l are 0 or
 1. 11. The method asset forth in claim 10, wherein the dioxabicyclo[3.3.0]octane derivativeis sesamin, sesaminol, episesamin, episesaminol, sesamolin,2-(3,4-methylenedioxy-phenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.12. The method according to claim 10, wherein a compound of the formula(I) is incorporated into a food or drink.
 13. A method of acceleratingthe lowering of a serum alcohol level increased by an intake of alcohol,comprising administering to a person in need of such treatment, aneffective amount to accelerate the lowering of a serum alcohol levelincreased by an intake of alcohol of a dioxabicyclo[3.3.0]octanederivative represented by the following general formula (I): ##STR6##wherein R¹, R², R³, R⁴, R⁵ and R⁶ independently represent a hydrogenatom or an alkyl group having 1 to 3 carbon atoms, or R¹ and R² and/orR⁴ and R⁵ together form a methylene group or an ethylene group, and n, mand l are 0 or
 1. 14. The method as set forth in claim 13, wherein thedioxabicyclo[3.3.0]octane derivative is sesamin, sesaminol, episesamin,episesaminol, sesamolin,2-(3,4-methylenedioxy-phenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane,2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.15. The method according to claim 13, wherein a compound of the formula(I) is incorporated into a food or drink.
 16. A method of lowering acholesterol or triglyceride level in the plasma, comprisingadministering to a person in need of such treatment an effective amountto lower a cholesterol or triglyceride level in the plasma ofdioxabicyclo[3.3.0]octane derivative represented by the followinggeneral formula (I): ##STR7## wherein R¹, R², R³, R⁴, R⁵ and R⁶independently represent a hydrogen atom or an alkyl group having 1 to 3carbon atoms, or R¹ and R² and/or R⁴ and R⁵ together form a methylenegroup or an ethylene group, and n, m and l are 0 or
 1. 17. The method asset forth in claim 16, wherein the dioxabicyclo[3.3.0]octane derivativeis sesamin, sesaminol, episesamin, episesaminol, sesamolin,2-(3,4-methylenedioxy-phenyl)-6-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane, 2,6-bis-(3-methoxy-4-hydroxyphenyl)-3,7-dioxabicyclo[3.3.0]octane or 2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-hydroxyphenoxy)-3,7-dioxabicyclo[3.3.0]octane.18. The method according to claim 16, wherein a compound of the formula(I) is incorporated into a food or drink.